it really depends on what you're trying to accomplish-- -- for wireframes, showing what info in what form, and information design sketches: omnigraffle, indesi

it really depends on what you're trying to accomplish-- -- for wireframes, showing what info in what form, and information design sketches: omnigraffle, indesign -- for full-on mockups, prototyping ui elements that need more polish, typography and overall design comps: photoshop/illustrator -- for interactive prototyping, demonstrating an interaction paradigm: html/prototype/scriptaculous, dreamweaver's templated JS functions (MM_swapimg, etc), or a good-old-fashioned paper prototype/whiteboard Your project will require one or more of these different fidelities of prototype, depending on what you have in mind.